Project Summary ? Overall 'Investigation of targets, mechanisms, and optimal delivery of therapeutic ketosis for functional longevity and treatment of Alzheimer's disease' We recently demonstrated, for the first time anywhere, that the isocaloric continuous Ketogenic diet extends cognitive and memory and muscle functions in mice, and significantly increases median longevity by 13%1. In the same issue of Cell Metabolism, others showed that the intermittent Ketogenic diet (iKD) preserves many late life functions in mice. These simultaneously-published findings have profound mechanistic (for understanding the biology of aging) and translational (for US public health) implications. Mechanistically, they suggest the hypothesis that 'ketosis delays aging'. The PPG application is designed to identify mechanistic targets and biomarkers by which therapeutic ketosis delays aging in mice, and are consistent with the geroscience concept, i.e. that interventions that delay aging should delay age related disease, in this case AD, Alzheimer's. By identifying the KD mechanisms and biomarkers in mice, this study will lay the ground work for future human studies. In order to serve these mechanistic and translational goals, we propose these four projects. 1, Cortopassi, involves the mechanistic dissection of the ketolongevity mechanism, using transcriptomics, protein arrays and knockout mice, and Shc antagonists for Alzheimer's disease. 2, Pelicci, maps the epigenetic consequences of aging, and how the KD reverses them, and to what extent these overlap with aging and Alzheimer's. 3, Baar, addresses KAT and acetylation mechanisms by which improved muscle function delays brain aging in wild-type and Alzheimer's mouse model. 4, Ramsey, identifies the 'ketotherapeutic envelope' necessary for preservation of late-life functions and longevity, and with respect to an Alzheimer's mouse model. These Projects are all interactive as shown in the text. They are also supported by an outstanding Animal Core C, led by Kent Lloyd DVM PHD and Lee-Way Jin MD PHD with stellar experience in mouse biology and Alzheimer's disease, brilliant support by Biostatistics Core B, Kyoungmi Kim, and a well- organized Administrative Core A. The completion of this project will lead to new mechanistic inside into the therapeutic ketosis longevity mechanism, and identify biomarkers of ketotherapeutic effect that could be relevant to preservation of functions and longevity in aging Americans, and those with Alzheimer's disease.